Major depression disorder is a significant health problem and behind the cardiovascular disease, depression is considered as the second most debilitating disease in the world. Selective serotonin reuptake inhibitors (SSRIs) antidepressant agents have been limited by slow onset of action and also have been implicated recently in high adolescent suicide rate and other side effects. In spite of developments of different array of antidepressants, there still remains a significant unmet need for much more improved therapy, as large numbers of depressed people are still refractory to the current existing therapies. Ironically, in the current pharmacotherapy of depression, dopaminergic component has not been included when there are ample clinical and biochemical evidences pointing towards a strong dopaminergic component in depression. Recently, triple monoamine uptake inhibitors (TUI) interacting with dopamine, serotonin and norepinephrine transporters have been implicated in potent antidepressant activity. This is due to the fact that additional dopaminergic component can effectively relieve depression by activating mesocorticolimbic dopaminergic pathways in the reward system. This can act to reduce anhedonia, which is associated with a deficit in dopaminergic transmission and is a central component to a depressive state of mind. In our effort to discover and develop novel molecules for interaction with multiple monoamine transporters, we have recently developed asymmetric di- and tri- substituted pyran derivatives. Uptake inhibition studies with all three monoamine transporters indicated variety of activities depending upon the nature of substitutions either on the pyran ring or on the N-benzyl moiety. The preliminary results also indicated stereospecific requirement for interaction of these molecules with the monoamine transporters as the potent interaction was mostly exhibited in the (-)-isomers. Three different classes of molecules emerged from these studies and they are labeled as serotonin-norepinephrine reuptake inhibitors (SNRI), NRI and triple reuptake inhibitors (TUI). One of the lead TUI molecules, (-)-17a, exhibiting potent norepinephrine and serotonin inhibition (Ki;5.09 and 37.7 nM, respectively) activity along with modest dopamine transporters uptake inhibition activity (Ki;85 nM), was further evaluated in different in vivo depression animal model studies. In vivo results indicated (-)-17a could potently reduce immobility in rat forced swimm test and mice tail suspension test. Furthermore, locomotor activity results indicated that this reduction of immobility was not due to locomotor activation. We now plan to follow up on our preliminary SAR studies on these pyran derivatives to develop more suitable TUI lead molecules. Lead compounds with suitable properties will be evaluated for antidepressant properties in animal experiments. Two most potent antidepressant molecules will be tested for their antianxiety effect and also on expression of brain derived neurotrophic factor (BDNF), implicated in the clinical action of antidepressant drugs. PUBLIC HEALTH RELEVANCE: Major depression disorder is a significant health problem and behind cardiovascular disease, depression is considered the second most debilitating disease in the world. Unipolar depression is ranked as number one before all other somatic and psychiatric illnesses. It is believed that at least 20% of all individual suffer from a depressive episode at least once in their lifetime. Depression is potentially fatal since most sufferers consider life threatening acts and suicide. Current therapy for depression is far less than ideal, as many patients suffering from depression remain symptomatic in spite of intensive treatment. In a recent study and from other observations, it has been demonstrated that majority of patient enrolled in a depression clinics did not attain full remission with existing antidepressants. This proposal addresses one of the key missing components in the current antidepressant therapy, which is the role of dopamine in depression. It is hypothesized in this application that molecules with triple monoamine uptake inhibitory activity incorporated in a calibrated way will provide more effective antidepressant action compared to antidepressants targeting only serotonin and norepinephrine systems.